The present invention relates to benzimidazole compounds useful as active ingredients of medicaments.
In recent years, patients with so-called adult diseases such as arterial sclerosis, hypertension, and diabetes mellitus have been continuously increasing with prolongation of life expectancy. In particular, patients with hyperlipidemia and arterial sclerosis derived therefrom have been remarkably increasing due to excessive intake of high calorie and high cholesterol food, which have become a serious social problem. Medications currently applied for treatment of hyperlipidemia and arterial sclerosis are those symptomatically lower cholesterol in blood, and no medicament that can be expected to have potency in retracting arterial sclerosis lesions has been used clinically. Arterial sclerosis is characterized by lesions of intimal hyperplasia and lipid accumulation in blood vessels, and it has been elucidated from recent biochemical findings that foaming of macrophages plays a main role in the formation of arterial sclerosis lesions. Accordingly, suppression of the foaming of macrophages may possibly prevent arterial sclerosis by inhibiting formation of arterial sclerosis lesions, or achieve radicular treatment of arterial sclerosis by retraction of arterial sclerosis lesions. However, no medicament having such activity has been known.
It has been suggested that an inhibitor of ACAT, an enzyme involved in intestinal absorption and metabolism of cholesterol, such as imidazole derivatives described in Bio. Med. Chem. Lett., Vol. 5(2), 167-172 (1995) reduces blood cholesterol level and thus suppresses the foaming of macrophages in an animal experiment (for example, piperazine derivatives described in International Publication WO98/54153). However, since these compounds are directed to ACAT inhibitory activity, they do not achieve satisfactory inhibition of the foaming of macrophages, and their effects are insufficient.
Some amide compounds are reported to have ACAT inhibitory action (for example, the amide compounds disclosed in International Publication WO99/25712). However, ACAT inhibitors have recently been recognized to have various toxicities and side effects (for example, Toxycol. Pharmacol., 22, 510-518 (1994); Toxicol. Appl. Pharmacol., 140, 387-392 (1996)). It is considered that medicaments for treatment of arteriosclerosis, which are required to be administered for a long period of time, advantageously have no ACAT inhibitory action with such side effects.
Some benzimidazole compounds are suggested to suppress the foaming of macrophages (for example, the imidazole compounds disclosed in EP849259). However, the compounds are not satisfactory in suppression of the foaming of macrophages and they fail to exert potent effect in vivo because their uptakes into animal bodies are very poor. As medicaments for treatment of arteriosclerosis or hyperlipidemia are taken by patients for a long period of time at home, the medicaments are required to be developed as oral preparations. Therefore, it is essential that these medicaments give a high value of AUC (area under the plasma concentration) that relates to uptake into living bodies through oral administration. However, the conventional imidazole compounds have a problem of poor oral absorbability.
An object of the present invention is to provide a compound having activity of suppressing the foaming of macrophages, and is useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of arterial sclerosis. Another object of the present invention is to provide a compound having the aforementioned activity, and is useful as an active ingredient of medicament for preventive and/or therapeutic treatment of hyperlipidemia. In particular, the object of the present invention is to provide a compound that can achieve the desired therapeutic effect by oral administration.
The inventors of the present invention conducted various researches to achieve the foregoing objects, and as a result, they found that novel benzimidazole compounds represented by the formula (I) set out below have activity of suppressing the foaming of macrophages, and are useful as active ingredients of preventive and/or therapeutic medicament of arterial sclerosis and preventive and/or therapeutic medicament of hyperlipidemia. They also found that these compounds can readily be uptaken into living bodies and exert superior therapeutic effect by oral administration. The present invention was achieved on the basis of these findings.
The present invention thus provides benzimidazole compounds represented by the following formula (I): 
[in the formula, R1 represents one or more functional groups on the benzene ring selected from the group consisting of hydrogen atom, a halogen atom, a lower alkyl group, and a lower alkoxy group; R2 represents hydrogen atom, an alkyl group, or an acyl group; L represents a C4-C8 alkylene group or an ethyleneoxy linking group represented by (CH2CH2O)nCH2CH2 (in the formula, n represents 1 or 2); X represents O or NH (NH may have a functional group on the nitrogen atom); Y represents S or a single bond; and Q represents a 5- or 6-membered heterocyclic group which may have a functional group on the ring (the heterocyclic group may have a condensed ring)] and salts thereof.
According to preferred embodiments of the present invention, provided are the aforementioned compounds and salts thereof, wherein Y is S; the aforementioned compounds and salts thereof, wherein R1 and R2 represent hydrogen atom; the aforementioned compounds and salts thereof, wherein L is a C4-C8 alkylene group; the aforementioned compounds and salts thereof, wherein Q is a residue of a heterocyclic ring selected from the group consisting of pyridine, pyrimidine, pyrazine, triazine, quinoline, pyrrole, thiophene, furan, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, benzimidazole, benzoxazole, and benzothiazole; the aforementioned compounds and salts thereof, wherein X is O; and the aforementioned compounds and salts thereof, wherein Q is a residue of a heterocyclic ring selected from the group consisting of pyridine, thiazole, benzimidazole, benzoxazole and benzothiazole.
As other aspects of the present invention, provided are methods for preparing the compounds represented by the aforementioned formula (I), and medicaments comprising a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient. As preferred embodiments of the aforementioned medicaments, pharmaceutical compositions are provided which comprise the aforementioned compounds or a physiologically acceptable salt thereof as an active ingredient and an additive for pharmaceutical preparation. The medicaments of the present invention are useful as, for example, those for preventive and/or therapeutic treatment of hyperlipidemia and for preventive and/or therapeutic treatment of arteriosclerosis. The medicaments are also useful as agents for suppressing foaming of macrophages, agents for retracting arterial sclerosis lesions, and agents for inhibiting formation of arteriosclerotic lesion.
As further aspects of the present invention, provided are uses of the compounds represented by the aforementioned formula (I) or salts thereof for manufacture of the aforementioned medicaments, and methods for preventive and/or therapeutic treatment of hyperlipidemia and methods for preventive and/or therapeutic treatment of arteriosclerosis, which comprise the step of administering a preventively and/or therapeutically effective amount of the compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human.
In the specification, a lower alkyl group or a lower alkyl moiety of a functional group that contains the lower alkyl moiety (e.g., lower alkoxy group) may be a linear, branched or cyclic alkyl group, or a combination thereof. For example, an alkyl group having 1-4 carbon atoms (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group and the like) may be used. A halogen atom referred to in the specification may be any of fluorine atom, chlorine atom, bromine atom and iodine atom.
An alkyl group or an alkyl moiety of a functional group that contains the alkyl moiety (e.g., an alkoxy group, an alkanoyl group, an alkylthio group and the like) referred to in the specification may be linear, branched or cyclic alkyl group, or a combination thereof. An example includes an alkyl group having 1-8 carbon atoms (e.g., methyl group, ethyl group, butyl group, octyl group and the like), and a preferred example includes an alkyl group having 14 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, n-butyl group). An aryl group or an aryl moiety of a functional group that contains the aryl moiety (arylcarbonyl group and the like) is preferably a monocyclic or bicyclic aryl group having a 6- to 10-membered ring, and more specifically, phenyl group, naphthyl group and the like can be used. An alkyl group or an alkyl moiety of a functional group having the alkyl moiety, a lower alkyl group or a lower alkyl moiety of the functional group having the lower alkyl moiety, or an aryl group may have one or two functional groups at any positions. When two or more functional groups exist, they may be the same or different.
Examples of the acyl group include an alkanoyl group, an arylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, a carbamoyl group and the like. Examples of the alkanoyl group include an alkanoyl group having 1-8 carbon atoms (e.g., acetyl group, butanoyl group, octanoyl group and the like), preferably an alkanoyl group having 1-4 carbon atoms (e.g., acetyl group, butanoyl group and the like). Examples of the arylcarbonyl group include an arylcarbonyl group having 6-10 carbon atoms (e.g., benzoyl group, naphthoyl group and the like). Examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 1-8 carbon atoms (e.g., methoxycarbonyl group, ethoxycarbonyl group, octyloxycarbonyl group and the like), preferably an alkoxycarbonyl group having 1-4 carbon atoms (e.g., methoxycarbonyl group, ethoxycarbonyl group and the like).
Examples of the alkylsulfonyl group include an alkylsulfonyl group having 1-8 carbon atoms (e.g., methanesulfonyl group, butanesulfonyl group, octanesulfonyl group and the like) and examples of the arylsulfonyl group include an arylsulfonyl group having 6-10 carbon atoms (e.g., benzenesulfonyl group, naphthalenesulfonyl group and the like). Examples of the sulfamoyl group include a sulfamoyl group having 0-8 carbon atoms (e.g., sulfamoyl group, methylsulfamoyl group, diethylsulfamoyl group, octylsulfamoyl group, hexadecylsulfamoyl group, phenylsulfamoyl group and the like), preferably a sulfamoyl group having 0-4 carbon atoms (e.g., sulfamoyl group, methylsulfamoyl group, diethylsulfamoyl group and the like). Examples of the carbamoyl group include a carbamoyl group having 0-8 carbon atoms (e.g., carbamoyl group, methylcarbamoyl group, diethylcarbamoyl group, octylcarbamoyl group, hexadecylcarbamoyl group, phenylcarbamoyl group and the like), preferably a carbamoyl group having 0-4 carbon atoms (e.g., methylcarbamoyl group, diethylcarbamoyl group and the like). The aforementioned acyl group may have on or more functional groups at any position. When two or more functional groups exist, they may be the same or different.
R1 represents one or more functional groups on the benzene ring selected from the group consisting of hydrogen atom, a halogen atom, a lower alkyl group, and a lower alkoxy group. When R1 represents two or more functional groups, they may be the same or different, and substitution positions on the benzene ring are not also particularly limited. The halogen atom represented by R1 may preferably be fluorine atom, chlorine atom, or bromine atom. R1 may preferably be hydrogen atom, methyl group, methoxy group, or chlorine atom, and more preferably hydrogen atom.
R2 is preferably hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkanoyl group, and most preferably hydrogen atom. L represents a linking group, and more specifically a C4-C8 alkylene group (e.g., butylene group, pentamethylene group, hexamethylene group, octamethylene group and the like) or an ethyleneoxy linking group represented by (CH2CH2O)nCH2CH2 (in the formula, n represents 1 or 2). These linking groups may be linear or branched. The linking group represented by L is preferably a C5-C8 alkylene group (pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group and the like) or the aforementioned ethyleneoxy bridging group, and most preferably a C5-C6 alkylene group. Y is preferably S. X is preferably O or NH, and NH may have a functional group on the nitrogen atom. Although kind of the functional group is not particularly limited, for example, a C1-C4 alkyl group, a C1-C4 alkanoyl group and so forth can be used. X is preferably O.
Q represents a 5- or 6-membered heterocyclic group which contains one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. The heterocyclic ring may be saturated or partially saturated, or an aromatic heterocyclic ring. Further, the heterocyclic ring may be condensed with a benzene ring or another heterocyclic ring. The heterocyclic group may have one or more functional groups on the ring. Examples of the functional group include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, nitro group, an amino group, an acylamino group, a sulfonamide group, an alkoxycarbonyl group, a carbamoyl group, an alkoxy group, an aryloxy group, hydroxy group, an alkylthio group, an arylthio group, mercapto group, cyano group, oxo group, thioxo group, and oxide on a nitrogen atom or a sulfur atom and so forth.
Examples of the heterocyclic ring constituting the heterocyclic group represent by Q include,for example, pyridine (e.g., 2-pyridyl, 4-pyridyl group), pyrimidine (e.g., 2-pyrimidyl, 3-pyrimidyl group), pyrazine (e.g., 2-pyrazyl group), triazine (e.g., 1,2,4-triazyl group), quinoline (e.g., 2-quinolyl, 4-quinolyl, 8-quinolyl group), pyrrole (e.g., 2-pyrrolo group), thiophene (e.g., 2-thienyl group), furan (e.g., 2-furyl group), imidazole (e.g., 2-imidazolyl group), pyrazole (e.g., 3-pyrazolyl group), triazole (e.g., 1,2,4-triazo-3-yl group), tetrazole (e.g., 1,2,3,4-tetrazo-5-yl group), thiazole (e.g., 2-thiazolyl group, 3-isothiazolyl group, 5-isothiazolyl group), thiadiazole (e.g., 2-thiadiazolyl group), oxazole (e.g., 2-oxazolyl group, 3-isooxazolyl group), oxadiazole (e.g., 2-oxadiazolyl group), benzimidazole (e.g., 2-benzimidazolyl), benzoxazole (e.g., 2-benzoxazolyl), benzothiazole (2-benzothiazolyl) and the like. Q is preferably a 5- or 6-membered heterocyclic group containing one or more nitrogen atoms (which may have a condensed ring). The heterocyclic ring that constitutes the heterocyclic group is most preferably pyridine, thiazole, benzimidazole, benzoxazole or benzothiazole.
Preferred compounds according to the present invention will be exemplified below. However, the scope of the present invention is not limited to these examples.
The compounds of the present invention represented by the aforementioned formulas (I) may form acid addition salts, and such acid addition salts fall within the scope of the present invention. Examples of the acid addition salts include, for example, mineral acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, and phosphates, and organic acid salts such as p-toluenesulfonates, methanesulfonates, oxalates, tartrates, malates, and citrates. Further, depending on the type of a functional group, they may also form base addition salts. Furthermore, the compounds of the present invention and salts thereof may exist as hydrates or solvates. Any of the compounds in free forms or in the forms of salts, and hydrates and solvates thereof falls within the scope of the present invention.
The compounds of the present invention may have one or more asymmetric carbons depending on the kind of a functional group. In such compounds, steroisomers such as optical isomers based on one or more asymmetric carbons and diastereoisomers based on two or more asymmetric carbons may exist. Any of stereoisomers in pure forms, any mixtures of the stereoisomers, racemates and the like fall within the scope of the present invention.
The compounds of the present invention can be prepared from readily available raw material compounds by methods well known to those skilled in the art, for example, in accordance with the following scheme. Specific procedures of these methods are explained in detail in the examples of the specification, and those skilled in the art can easily produce the compounds of the present invention by referring to the general explanations given below and the examples, and by adding suitable alterations or modifications to these methods as required (the symbols used in the scheme have the same meanings as those defined above). 
Where Y is S and X is O, a 2-mercaptobenzimidazole derivative (a) and a halide alcohol (b) having a linking chain (L) (as the halide, chloride, bromide, iodide or the like can be used, and a sulfonate such as tosylate or methanesulfonate may also be used instead of the halide; specific examples thereof include 5-bromo-1-pentanol and the like) are reacted to obtain a compound (c) (Xxe2x80x2=O). As a solvent, alcohols, acetonitrile and the like can be used, and reaction temperature may be from room temperature to 150xc2x0 C., preferably about 50xc2x0 C. to 120xc2x0 C. Further, when a base such as triethylamine is used as an acid scavenger, the reaction may sometimes progress faster, thereby the reaction temperature may be lowered and the reaction time may be shortened. The compound (c) can be reacted with a halide of heterocyclic ring (e.g., 2-chloropyridine and the like) under an alkaline condition to obtain a compound (d) (X=O). The reaction can be carried out by using a caustic alkali in a solvent such as dimethyl sulfoxide (DMSO), and the reaction temperature is about 100xc2x0 C. to 160xc2x0 C. Where a crown ether or the like is used for the reaction, the reaction may sometimes be markedly promoted.
Further, opposite to the aforementioned steps, a compound (d) can also be produced by reacting a halide of heterocyclic ring (e.g., 2-chloropyridine and the like) with a diol compound having a linking group (L) (e.g., 1,5-pentanediol) to produce an alcohol compound in which one of hydroxyl groups is replaced with a heterocyclyloxy group, and then converting the alcohol into a sulfonate in a conventional manner, and further reacting the sulfonate with 2-mercaptobenzimidazole. The reaction of the halide of heterocyclic ring and the diol compound can be preferably performed by using metallic sodium, potassium t-butoxide, sodium methylate or the like as a base catalyst at about xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C., in a solvent such as tetrahydrofuran (THF), dimethylacetamide (DMAc), DMSO or the like. As the sulfonate, tosylate or methanesulfonate can be used. The reaction of the sulfonate and 2-mercaptobenzimidazole can be performed in a solvent such as alcohols and acetonitrile at room temperature to 150xc2x0 C., preferably about 50xc2x0 C. to 120xc2x0 C. When a base such as triethylamine is used as an acid scavenger, the reaction may sometimes progress faster, thereby the reaction temperature may be lowered and the reaction time may be shortened.
Where Y is S and X is NH, a 2-mercaptobenzimidazole derivative (a) and a compound (b) having a linking chain (L) (bi-functional halogeno compound such as chloride, bromide or iodide, sulfonate compound such as tosylate or methanesulfonate or the like, more specifically, dibromopentane, bis-2-chloroethyl ether or the like) are reacted to obtain a compound (c) in which one of functional groups is replaced with the 2-mercaptobenzimidazole derivative. As a solvent, alcohols, acetonitrile and the like can be used, and reaction temperature may be from room temperature to 150xc2x0 C., preferably about 50xc2x0 C. to 120xc2x0 C. Further, when a base such as triethylamine is used as an acid scavenger, the reaction may sometimes progress faster, thereby the reaction temperature may be lowered and the reaction time may be shortened.
The compound (b) wherein only one of the functional groups is a halide or sulfonate is subjected to the reaction (the remaining functional group may optionally be hydroxyl group, acetate moiety or the like, and the reaction condition for said compound may be the same as that mentioned above), and then the resulting compound (c) is subjected to substitution of Xxe2x80x2 with a halide or sulfonate. For example, substitution from hydroxyl group to a halide or sulfonate can be conducted by a conventional method utilizing tosyl chloride, carbon tetrabromide/triphenylphosphine or the like. NH group of the compound (c) as a halide or sulfonate is protected with a silyl group, methoxymethyl group or the like, and then the product is reacted with an aminoheterocyclic ring, and the protective group can be removed to obtain a compound (d) (X=NH). This reaction can be performed by using a base catalyst, preferably sodium hydride, and dimethylformamide (DMF), DMAc, DMSO, dimethyl-imidazolinone or the like as a solvent at 0xc2x0 C. to 50xc2x0 C.
As another route, a compound (c) (Xxe2x80x2=halogen) can be reacted with potassium phthalimide and immediately hydrolyzed by using hydrazine hydrate to obtain an amino compound (c) (Xxe2x80x2=NH2). The amino compound can be reacted with a halide of heterocyclic ring (e.g., 2-chlorobenzothiazole and the like) to obtain a compound (d) (X=NH).
Where Y is a single bond, a target compound (g) can be obtained by cyclizing o-phenylenediamine (e) and a hydroxyalkylcarboxylic acid or an ester thereof by condensation under an acidic condition to form a benzimidazole ring to produce a compound (f), and then reacting the resulting product with a halide of heterocyclic ring under an alkaline condition in the same manner as mentioned above. The reaction of o-phenylenediamine (e) and the hydroxyalkylcarboxylic acid or an ester compound thereof can be performed by heating them to 120xc2x0 C. to 150xc2x0 C. in aqueous hydrochloric acid.
The compounds of the present invention have a potent activity of suppressing the foaming of macrophages which is involved in the formation of arterial sclerosis lesions in arterial sclerosis. Therefore, the compounds are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of arterial sclerosis, and an active ingredient of a medicament for preventive and/or therapeutic treatment of hyperlipidemia by lowering blood cholesterol. Although it is not intended to be bound by any specific theory, it has been known that invasion of foamed macrophages into arterial walls triggers hyperplasia of smooth muscles of arterial walls, thereby causing arterial sclerosis (Schaffner, T. et al., Amer. J. Pathol., 110, pp.57-73, 1980; Gerrity, R. G., Amer. J. Pathol. 103, pp.181-190, 1981). The medicaments of the present invention directly inhibit the formation of arterial sclerosis lesions and enables retraction of arterial sclerosis lesions by suppressing the foaming of macrophages which is involved in the formation of arterial sclerosis lesions. Accordingly, the medicaments of the present invention are useful for prevention and/or treatment of arterial sclerosis and hyperlipidemia brought by various causes.
As the active ingredients of the medicaments of the present invention, a substance selected from the group consisting of the compounds represented by the aforementioned formula (I) and salts thereof, and hydrates thereof and solvates thereof can be used. Routes of administration of the aforementioned medicament are not particularly limited, and they can be administered orally or parenterally. Oral administration is preferred. Although the aforementioned substance as the active ingredient, per se, may be used as the medicament of the present invention, it is generally desirable to provide the medicament as a pharmaceutical composition in a form well known to those skilled in the art by adding pharmaceutical additives as required.
Examples of the pharmaceutical composition suitable for oral administration include, for example, tablets, capsules, powders, subtilized granules, granules, solutions, syrups and the like. Examples of the pharmaceutical composition suitable for parenteral administration include, for example, injections, fusion drips, suppositories, inhalants, transdermal preparations, transmucosal preparations, patches and the like. As the pharmaceutical additives, excipients, disintegrating agents or dissolving aids, isotonic agents, pH modifiers, stabilizers, propellants, tackifiers and the like can be used, and they can optionally be used in combination.
For example, for the manufacture of the pharmaceutical composition suitable for oral administration, transdermal administration, or transmucosal administration, usable pharmaceutical additives include excipients such as glucose, lactose, D-mannitol, starch and crystalline cellulose; excipients or disintegrating aids such as carboxymethyl cellulose, starch and carboxymethyl cellulose calcium; binders such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and gelatin; lubricants such as magnesium stearate and talc; coating agents such as hydroxypropylmethyl cellulose, sucrose, polyethylene glycol and titanium oxide; bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaoline, glycerol, purified water and hard fat and the like. Further, the pharmaceutical composition can also be produced by using pharmaceutical additives such as, for example, propellants such as frons, diethyl ether and compressed gases; tackifiers such as sodium polyacrylate, polyvinyl alcohol, methyl cellulose, polyisobutylene and polybutene; base fabrics such as cotton cloth, and plastic sheets and the like.
For preparation of the pharmaceutical composition suitable for injection or drip infusion, usable pharmaceutical additives include, for example, dissolving agents and dissolving aids that can form aqueous injections or injections that are dissolved upon use such as distilled water for injection, physiological saline and propylene glycol; isotonic agents such as glucose, sodium chloride, D-mannitol and glycerol; pH modifiers such as inorganic salts, organic acids, inorganic bases and organic bases and the like.
Doses of the medicament of the present invention are not particularly limited, and suitably chosen depending on dosage forms, purpose of administration, i.e., preventive and/or therapeutic purpose, the age, body weight, and symptoms of a patient and the like. For example, for intravenous administration, about 10 mg to 400 mg per day for an adult as the amount of an active ingredient can be administered, and for oral administration, about 10 mg to 800 mg per day for an adult as the amount of an active ingredient can be administered. Preferred doses for an adult are 10 mg to 100 mg per day and 10 mg to 300 mg per day, respectively, as the amount of an active ingredient. The medicament of the present invention may be administered once or several times a day, and any administration period may be applied depending on the age of a patient and improvement of symptoms and the like.